CZ321496A3 - Novel erythromycin derivatives, process of their preparation and their use as medicaments - Google Patents

Abstract

Erythromycin derivs. of formula (I) and their acid addn. salts, are new. R = -(CH2)nAr; n = 3 - 5; Ar = heterocyclic gp. (opt. substd. one or more times) (37 gps shown in specification); or R = a gp. (i); Z = H or an acid residue. Ar can also be a gp. (a)-(e) (opt. substd.); R can also be a gp. (ii) or (iii); (opt. substd.). Also claimed are amines RNH2 (III) and their acid addn. salts.

Description

Area Ůč-c ^ / ιΓ ^,

The present invention relates to novel erythromycin derivatives, their preparation and use as medicaments.

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SUMMARY OF THE INVENTION

The present invention provides compounds of formula (I) '

wherein R is - (CH _{t) fl} Ar radical in which n is 3,4 or 5 and Ar represents a heterocyclic radical, optionally having one or two substituents selected from the following skupinbradikálů:

a radical or R is and Z is a hydrogen atom or an acid residue, as well as acid addition salts thereof.

Examples of addition salts of these derivatives with mineral or organic acids include salts of acetic, propionic, trifluoroacetic, maleic, tartaric, methanesulfonic, benzenesulfonic, p-toluenesulfonic, hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric and especially stearic, ethyl succinate. and laurylsir.

The heterocyclic radical may be substituted with one or more radicals selected from the group consisting of free, neutralized, esterified and amidated carboxyl radicals, hydroxyl radicals, halogen atoms, NC radicals, C = N radicals, linear, branched or cyclic alkyl radicals, linear or branched alkenyl or alkynyl radicals and further radicals: O-alkyl, O-alkenyl and O-alkynyl, Salkyl, S-alkenyl or S-alkynyl and N-alkyl, N-alkenyl and Nalkynyl containing up to 12 carbon atoms optionally substituted by one or more halogen atoms , radical, R and R _9, identical or different, meaning hydrogen or an alkyl radical containing up to 12 carbon atoms, carbocyclic aryl, or O-aryl. S-aryl radicals or heterocyclic aryl; O-aryl or S-aryl radicals containing one or more heteroatoms, optionally substituted with one or more of the above substituents, and

-C-R radical, Rj is an alkyl radical containing up to 12 carbon atoms or an optionally substituted carbocyclic or heterocyclic aryl radical.

When a heterocyclic radical contains several rings (fused or fused) the substituent or substituents may be on one and / or another of the heterocyclic or carbocyclic rings; for example, if the heterocyclic ring is attached or fused to an aryl radical, the heterocyclic ring and the aryl ring may have one or more substituents.

The aryl radical is preferably a phenyl or naphthyl radical,

the alkyl, alkenyl or alkynyl radical is preferably one of the following radicals: methyl, ethyl, propyl isopropyl, n-butyl, isobutyl, terbutyl, decyl or dodecyl, vinyl, allyl, ethynyl, propynyl, propargyl, cyclobentyl, cyclopentyl or cyclohexyl,

- the halogen is preferably fluorine, chlorine or bromine,

- the alkyl radical substituted with a halogen atom is preferably one of the following radicals: CHCl3, CHBr4, CHF4, CCl4, CBr4, CF *, CH3 CF3, CH3CH3C1, CH3CH3C4,

the carboxylic acid residue is preferably an acetyl, propionyl, butyryl, isobutyryl, n-valeryl, isovaleryl, tertvaleryl and pivalyl residue.

The present invention further provides compounds of formula (I) wherein Z is a hydrogen atom and a compound of formula (I), wherein n is 4.

In addition, the present invention provides compounds of formula (I) wherein Ar is a radical

optionally substituted, as well as compounds of formula (I), wherein R is a radical

optionally substituted, as well as compounds of formula (I), wherein Ar is a radical

optionally substituted and especially compounds of formula (I) wherein Ar is an optionally substituted radical

A further object of the invention are compounds of formula (I), the preparation of which is described in the experimental section.

- 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11 (oxycarbonyl (( 4- (4-phenyl-1H-imidazol-1-yl) butyl) imino) erythromycin,

- 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11 (oxycarbonyl ((4- (3H-imidazo (4,5-b) pyridin-3-yl) butyl) imino)) erythromycin,

- 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11 (oxycarbonyl ((4- (1H-imidazo (4,5-b) pyridin-1-yl) butyl) imino)) erythromycin,

- 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11 (oxycarbonyl ((4- (4- (4-chlorophenyl) -1H-imidazol-1-yl) butyl) imino)) erythromycin,

- 11,12-dideoxy 3-de ({2,6-dideoxy-3-C-methyl-3-O-methylalpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11 (oxycarbonyl (( 4- (4- (2-methoxyphenyl) 1H-imidazol-1-yl) butyl) imino) erythromycin,

- 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11 (oxycarbones ((- (4- (4- (4-fluorophenyl) -1H-imidazol-1-yl) butyl) imino)) erythromycin,

- 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methylalpha-L-carbohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11 (oxycarbonyl {( 4- (7-methoxy-4-quinolinyl) butyl) imino}) erythromycin,

- 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methylalpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11 (oxycarbonyl (( 4- (2- (2-pyridinyl) 4-thiazolyl) butyl) imino) erythromycin,

- 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methylalpha-L-ribohexopyranosyl) oxy) 6-Q-methyl 3-oxo 12,11 (oxycarbonyl (( 4- (3- (3-pyridinyl) 1H-1,2,4-triazol-1-yl) butyl) imino) erythromycin, and in particular

11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L ribohexopyranosyl) oxy) 6-O-methyl. 3-oxo 12,11- (oxycarbonyl ((4- (4- (3-pyridinyl) 1H-imidazol-1-yl) butyl) imino)) erythromycin

The compounds of formula (I) show very good antibiotic activity against Gram positive bacteria such as staphylococci, streptococci and pneumococci.

Thus, the compounds of the invention may be used as medicaments in the treatment of infections caused by germs, in particular staphylococci such as staphylococcal speticemia, malignant skin or skin staphylococcal disease, pyodermitis, septic or septic ulcers, ulcers, anthrax, phlegmon, erysipelas and acne such as primary or post-influenza acute tonsillitis, bronchopneumonia, purulent pneumonia, streptococcal infections such as acute tonsillitis, otitis, nusitis, scalp, pneumococcal infections such as pneumonia, bronchitis, brucellosis, diphtheria, gonococcal infection.

The products of the invention are also active against infections caused by pathogens such as Haemophilus influenzae, Rickettsia, Mycoplasma pneumoniae, Chlamydia, Legionella, Ureaplasma, Toxoplasma or Mycobacterium, Listeria, Meningococcus and Campylobacter microorganisms.

For this reason, the invention also relates to medicaments, in particular antibiotic medicaments, products of formula (I) above, as well as their addition salts with pharmaceutically acceptable mineral or organic acids.

The invention furthermore relates to medicaments, in particular antibiotic medicaments, preferably the products of formula (I) above, in particular the products mentioned in Examples 1, 2, 3 and 29 to 35, as well as their pharmaceutically acceptable salts.

The invention further provides pharmaceutical compositions comprising the active ingredient of at least one of the above-mentioned drugs.

These compositions may be administered by the oral, rectal or parenteral route, or topically, as application to the skin and germs, but the oral route is always preferred.

The medicament may be in solid or liquid form, as is commonly used for human medicine, i.e., plain or coated tablets, capsules, granules, suppositories, injectables; ointments, creams and gels; they are prepared according to conventional known methods. The active ingredients or ingredients may be formulated together with the usual exposures for the compaction of the ingredients. talk, gum arabic, lactose, starch, magnesium stearate, cocoa butter, non-aqueous vehicles, vegetable or animal fatty substances, paraffin derivatives, glycols, various humectants, dispersing or emulsifying agents, stabilizing agents.

Z ⁴

These compositions may also be formulated as a powder, which may be dissolved as desired in a suitable vehicle, e.g., pyrogen-free sterile water.

The dosage administered varies according to the nature of the disease being treated and the physical constitution of the patient, the mode of administration and also the product. E.g. the dose may be from 50 mg to 300 mg by the oral route in an adult human for the product of Example 1 or Example 2.

The invention further provides a process for the preparation of a compound of formula (I), characterized in that the compound of formula (II)

-)

(II) wherein Z 'is an acid residue, reacted with a compound of formula (III)

RNH, where R is as defined above, for the preparation of the compound δ-in the visor-

O (1A>

wherein R and Z 'are as defined above and, if desired, is treated with a compound of formula (fy) with a hydroxyl function agent at the 2' position and / or, if desired, treated with an acid to form a salt, which

- the reaction of the compound (II) with the compound of the formula (III) takes place in a solvent such as acetonitrile, dimethylformamide or also tetrahydrofuran, dimethoxyethane or dimethylsulfoxide,

- hydrolysis of the ester bond at position 2 'is carried out with methanol or aqueous hydrochloric acid,

salt formation is carried out with acids according to standard procedures.

The compounds of formula (II) used as starting products are described and claimed in European patent application 0,596,802.

The compounds of the formula RN are generally known products, however, the compounds used in the preparation of the products in the examples are novel and are themselves an object of the invention; their preparation is given below.

Compounds of formula (III)

(1982) Vol. 25, p. 947 et al., Tetrahedron Letters, Vol. 32, No 14, pp. 1699-1702. 19-91 -) - Org rGhem .-- 54-. (18). 42.98, 301, (1989); J.Org.Chem. 28 (101) 2589 91 (1963) or in German Patent 3,406,416; J. Org. Chem. 6-895-901 (1941) or

Synth. Commun 17 (14) 1741-8, (1987).

A particular object of the invention is the amines of formula (III) as defined above, the preparation of which is described in detail below.

The invention further provides:

- 4-Phenyl-1H-imidazole-1-butanamine,

- 3H-imidazo (4,5-b) -pyridine 3-butanamine

- 1H-imidazo (4,5-b) pyridine 3-butanamine, 2-phenyl-4-quinoline butanamine,

- 1H-benzotriazole. 1-butanamine,

- 2H-benzotriazole 2-butanamine,

- 1-methyl-1H-imidazo (4,5-c) pyridine 2-butanamine,

- 3-methyl-3H-imidazo (4,5-c) pyridine 2-butanamine,

- 5-chloro-1H-benzimidazole 1-butanamine,

- 7-methoxy-4-quinoline butanamine,

- 1H-imidazo (4,5-c) pyridine * 1-butanamine,

- 9H-purine 9-butanamine,

- 1-methyl-1H-indole 4-butanamine,

- 3-phenyl 1H-1,2,4-triazole 1-butanamine (hydrochloride),

- 5-phenyl 1H-tetrazole 1-butanamine (hydrochloride),

- 2-benzothiozole butanamine,

- 4- (thieno (2,3-b) pyridin-4-yl butanamine),

- 5,6-dimethyl 1H-benzimidazole 1-butanamine,

- 3-quinoline butanamine,

- 2-quinoline butanamine,

- 5H-Imidazo [4,5-c] pyridine 5-butanamine,

- 1-methyl 1H-benzimidazole 2-butanamine,

- 6-chloro-1H-benzimidazole 2-butanamine,

- 2-methyl-1H-benzimidazole 2-butanamine,

- 4- (4-chlorophenyl) -1'-imidazole-1-butanamine,

2- (3-pyridinyl) thiazole 5-butanamine?

- 7-methoxyquinoline 4-butanamine,

- 4- (4-fluoro; phenyl) 1H-imidazole 1-butanamine,

- 4- (2-methoxyphenyl) 1H-imidazole 1-butanamine,

- 3- (3-pyridinyl) 1H, 1,2,4-triazole 1-butanamine,

- 4- (3-pyridinyl) 1H-imidazole 1-butanamine,

- 2- (2-pyridinyl) thiazole 4-butanamine./

- 2-phenylthiazole 4-butanamine,

- 4- (4-methoxyphenyl) -4-imidazole 1-butanamine,

- isoquinoline 4-butanamine,

- quinazoline 4-butanamine ^,

- 4,5-diphenyl-1H-imidazole 1-butanamine,

- 4- (3-methoxyphenyl) 1H-imidazole 1-butanamine,

- 4- (4- (trifluoromethoxy) phenyl) im -imidazole 1-butanamine,

1,2,3,6-tetrahydro-1,3-dimethyl 2,6-dioxo 7H-purine. 7butanamine,

- 2- (4-pyridinyl) thiazole 4-butanamine,

- 1H-Indole 1-butanamine,

2- (3-pyridinyl) thiazole 4-butanamine, and their acid addition salts.

DETAILED DESCRIPTION OF THE INVENTION

Example 1: -j, 12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11- (oxycarbonyl ((4- (4-phenyl-1H-imidazol-1-yl) butyl) imino)) erythromycin

Mix 0.70'S g of 11-deoxy 10,11-dihydro-3-de (2,6-dideoxy 3-C-methyl 3-O-methyl alpha-L-ribohexopyranosyl) oxy) 12-O - ((1H-imidazole) -l-yl) carbonyl) 6-0-methyl 3-oxo eřýtřbmyďin ^_ '2 - ace-ta-t-.připravený as described in Example 1C of the European patent application EP 0,596,8022 in 3 ml of acetonitrile' with 10% of water and 1.08 g of 4- (4-phenyl-1H-imidazol-1-yl) butamine was heated to 63 ° C. The reaction mixture is kept at this temperature for 5 hours. After it is allowed to cool to ambient temperature, the reaction mixture is poured into a sodium phosphate solution, extraction is carried out with ethyl acetate. The organic phase was washed with water, dried, filtered and concentrated. 1.5 g of product are obtained, to which 210 ml of methanol are added. The reaction mixture was then stirred at room temperature under nitrogen for 16 hours. After concentration, 1.4 g of product are obtained which is chromatographed on silica gel, eluent CH 2 Cl 2 - MeOH NE. OH (93-7-0.4). After concentration, 0.305 g of crude product is obtained, which is recrystallized from isopropyl ether, then washed and dried at 50 DEG C. under reduced pressure. There was thus obtained 0.267 g of the desired product with a melting point of 222 DEG-231 DEG.

NMR CDCl 3 ppm alpha d = ^{+ 18} ° (c = ° · ⁹ CHCl 3)

0.84 (t): CH 3 -CH 2; 1.01 (d) -1.17 (d) -1.24 (d): / _CH3 ~ CH '1.30 (d) -1.38 (d) 1.34 1.47 FCO: 6 and 12 Me; 2.27 (s):

N (Me) ₂ ; 2.45 (-): H '₃; 2.61 (m): _H8; 2.63 (s): 6-OMe;

3.04 (-): H 4; 3.13 (q): _H10; 3.18 (dd): H- ₂ ; 3.53 (~): H 5;

3.56 (s): _Hn ; 3.67 (-) 3.75 (-): skup.-C-N-CH _2; 3.87 (q)

O

H ₂ ; 3.99 (t): _CH2 NC; 4.23 (d): _H5; 4.27 (d): H '1; 4.94 dd

H- | ₃ ; 7.26 (s): H 5; 7.5 (s): _H2; 7.20: H in para position;

7.35: H in meta position; 7.76: H in ortho position ...

Preparation 1: 4- (4-phenyl-1H-imidazol-1-yl) butanamine

Step A: 2- (4-) 4-phenyl-im-imidazol-1-yl) butyl ΙΗ-iso indole 1,3 (2H) dione

A solution containing 5.05 g of 4-phenyl-1H-imidazole in 25 cm dimethylformamide was added dropwise over 1 h and 30 min. it adds to the mixture 7 cm < 2 > cm < 3 > of dimethylformamide and sodium hydride. Then, 10.86 g of N-4-bromobutylphthalimide in a solution of 25 cm < 3 > dimethylformamide. The mixture is maintained at 70 DEG C. for about 1 hour and 30 minutes. After the mixture was allowed to cool to room temperature, the solution was concentrated, made up with water and extracted with ethyl acetate. The organic phase is washed with water. dried, filtered and concentrated. 15 g of product are recrystallized from ethyl acetate.

The product is collected, washed with ethyl acetate and dried under reduced pressure at 50 DEG C. Yield: 5.5 g of the desired product with a melting point of about 430 DEG-132 DEG.

NMR CDCl 3 ppm

1.75 (m) (2H) -1.86 (ra) (2H); 3.74 (t): H

4.03: 2H; 7.22 (fc): 2H H4; 7.26 (m): 1H H3; 7.36 (t): 2H H3 and _H5; 7.56 (d): H '₅; about 7.73 (m): 4H; approx. ⁷ · ⁸⁶ (m): H2 and Hg

Step B: 4- (4-phenyl-1H-imidazol-1-yl) butanamine

A mixture of 3.45 g of the product obtained in Step A, 100 ml of ethanol and 0.97 ml of hydrazine hydrate is maintained at reflux for 8 hours. The reaction mixture is concentrated, about 50 ml of 2N sodium carbonate are added, extraction is performed with ethyl acetate. The organic phase is washed with 2N sodium carbonate, then with sodium chloride. After drying, filtration and concentration, 2.21 g of the desired product is obtained.

^'H NMR CDC1 ₃ ppm

1.47 (m) - 1.87 (m): .cent. CH-2.73 (t), 3.97: -CH2 * NH2 <7.20 (d): H'3; 7.50 (d): H 5; 7.37 (wt) 2H: H 3 H 5; 7.24

1H: H4; 7.77 (m) 2H: H ₂ and Hg.

Example 2; 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha, -L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11 - ( oxycarbonyl ((4- (3H-imidazo (4,5-b) pyridin-3-yl) butyl) imino)) erythromycin.

11-deoxy 10,11-didehydro 3-de (2,6-dideoxy 3-methyl 3-O-methyl alpha-L-ribohexopyranosyl) oxy) 12-O - ((1H-imidazol-1-yl) carbonyl) 6-O-methyl 3-oxo erythromycin. The 2'-acetate prepared according to Example IC described in European patent application EP 0,596,802 and 958 mg of (3H-imidazo (4,5-b) pyridine-3-butanamine) are dissolved in 2.82 cm @ 3 of acetonitrile and 0.28 cm @ 3 of water.

The reaction mixture was heated to 80 ° C. Then it was allowed to cool to ambient temperature and poured into a solution of sodium phosphate acid. Extraction is performed with methylene chloride, followed by washing with water. The aqueous phases were collected and the extraction was repeated. After drying, filtering and washing, 826 mg of product is obtained. This product was dissolved in 16.5 cm ^{3 of} methanol. The reaction solution was stirred at ambient temperature for 20 h. 789 g of crude product was then purified by chromatography, eluting with a mixture of methylene chloride, methanol and ammonium hydroxide (94-6-0.4). 327 mg of the desired product of melting point 200 DEG C. alpha, _D = + 13 DEG C. = 1% CHCl3 NMR CDCl3 400 MHz ppm

0.85 (t): CH 3 -CH 2; 1.01 (dJ-1.16 (¢ 3) -1.25 (d): CH 2 -CH groups 1.30 (d) -1.26 (d), 1.35 and 1.47: 6 12 Me; approx. 2.27 (s):

N _{(CH3) 2;} 2.46 (m): H- ₃ ; about 2.59 (m): Hg; 2.61 (s): 6-OMe; 3.07 (m): H 4; 3.12 (wq): _H10 ; 3.18 (dd): H- ₂ ; 3.54 (m): H 1 _S ; 3.57 (s): Hi1; 3.6 to 3.8: CH ₂ NC; 3.85 (q): _H2; 4.24 (d): Hg; 4.29

O (d): H 1; approx. 4.35 (m): CH ₂ NC; 4.93 (dd): H ₁₃ ; 7.21 dd

II

H (>;. 8.04 (dd): H7 aromatic 8.71 (s): _H2; 8.38 (dd): H5.

Example 3 11,12-Dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo.

12,11- (oxycarbonyl ((4- (1H-imidase (AyS-b) -pyridin-1-yl) _____ butyl) imino)) erythromycin

708 mg 11-deoxy 10 ₍ 11-didehydro-3-de (2,6-dideoxy 3-C-methyl 3-O-methyl alpha-L-ribohexopyranosyl) oxy) 12-O - ((1H-imidazol-1-yl) carbonyl) 6-O-methyl 3-oxo-erythromycin 2'-acetate prepared as described in Example 1C of European Patent Application EP 0,596,802 is added to a solution containing 953 mg of (1H-imidazo (4,5-b) pyridine 3-butanamine, 2.82) cn? of acetonitrile and 0.28 cit? of water. the reaction mixture was warmed to 55 ⁱⁿ C, maintained at this temperature for 44 h., then add 0.5 CFZ acetonitrile. heating was continued at 55 C for 20 h. the reaction The mixture was allowed to cool to ambient temperature, then poured into saturated sodium phosphate solution, the aqueous phase was extracted with methylene chloride and the chloromethylene phases were washed with water, dried over sodium sulfate, filtered and evaporated to give 806 mg of product. 16.1 cm @ 3 of methanol are added and the reaction mixture is maintained at ambient temperature for 24 hours and evaporated s to dryness. There were obtained 656 mg of product which was purified by chromatography on silica gel, eluting with CH ₂ Cl ₂ -MeOH-N% (94-6-0.4).

The desired crude product was purified by silica gel chromatography, eluting with CHCl 3 -MeOH-NH 4 OH (94-6-0.4). After dissolution of the residue. in ethyl acetate-isopropyl ether, filtration and drying gave the desired product.

2.27 (s):

approx. 2.60 (m in mas

M.p. Mp 203 ° C.

α _D = 17.6 ° C = 1% CKCl 3.

0.81 (t): CH 3 -CH 2; 1.00 (d) -1.17 (d) -1.25 (¢3) -1.31 (d) -1.38 (d) CH-CH groups 1-35 (s) -1.47 (s): 6 and 12-CH3; 1.68 (m) and 1.93 (m): center of the CH3 chain;

N (CH 3) ₂ ; 2.61 (s): 6-OCH 3; 2.45 (m) Hooked Hg; 3.07 (m): H 4; about 3.15 (wg): H 1 q; 3.18 (dd): H- ₂ ; 3.56 (s): «η; 3.53 (m): H '_s; 3.60 a 3.80 (m): CO-N-CH _2; 3.87 (g): H _2; about 4.25 (m): CH ₂ -N =; 4.24 (d)

H ₅ ; 4. ^ 7d7: H ⁷ in "4; 9 ^" Tdd): ^ HY3; 7τ21 ~ (dd-, = -5-and..8) ': ______

Hg; 7.80 (dd, J = 8 and 1.5): aromatics H7-; 8.56 (dd, J = 5 and 1.5): Hg; 8.15 (s): H ₂ + CH ₂ Cl ₂ .

Preparation 2: Preparation of the amines used as starting products in Examples 2 and 3.

3H-imidazo (4,5-b) pyridine 3-butanamine and 1H-imidazo (4,5-n) pyridine 1-butanamine

Stage a:

10.3 g of potassium carbonate are added to a solution of 5.95 g of 4-azabenzimidazole and 15.5 g of N-4 bromobutylphthalimide in 30 cm of dimethylformamide. The mixture was stirred for 20 hours at ambient temperature. The insoluble portion was filtered off, washed with methylene chloride. The organic phase is washed with water, then dried over magnesium sulphate and evaporated; The oily residue is washed with petroleum ether and then with isopropyl ether. There was thus obtained 16.3 g of a crude product which was purified by silica gel chromatography, eluting with methylene chloride-acetone; 4.9 g of product (A) with a melting point of 143 ° C and 3.9 g of product (B) with a melting point of 172 ° C are obtained.

Step b1: 3H-imidazo (4,5-b) pyridine-3-butanamine (starting product of Example 2)

A mixture of 32.86 g of the product (A) prepared in the previous step, 697 cit? ethanol and 20 cm ^{3 of} hydrazine are stirred at reflux for 19 hours. The mixture is then allowed to cool to ambient temperature, filtered, washed and evaporated to dryness. The residue was dissolved in methylene chloride, filtered, washed and evaporated to dryness. 18.87 g of the expected product is obtained.

NMR CDCl 3 - 250 MHz ~ 752 '(m / z - 2 in O (m): -2-center group, 63_ (wide_s): 2-mobile H 2.76 (t): CH ₂ -CH ₂ -NH ₂ ; 4.33 (t): = CN-CH 2 CH 2

C = O

7.24 (dd, J = 8 and 5): Hg; 8.08 (dd, J = 8 and 1.5): γγ;

8.40 (dd, J = 5 and 1.5): _H5; 8.08 (s): H2.

Step b2: 1H-imidazo (4,5-b) pyridine 1-butanamine (starting product of Example 3)

A mixture of 32 g of product (B) from Preparation 3, 640 in ethanol and

24.8 crf? The hydrazine is stirred at reflux for 21 hours. Filtration, washing with ethanol and evaporation under reduced pressure are carried out. The residue was dissolved in methylene chloride, then filtered, washed and evaporated to dryness. 19.5 g of the expected product are obtained.

1.45 (m) -1.96 (m) CH 2; 2.74 (t): CH 2 -NH 2; approx. - 1.45 (m): mobile; 4.23 (t): C-N-CH2-CH2; 7.24 (dd,

C

And J = 8. 5): _H6; 7.75 (dd, J * 8 a. 1.5): _H7; 8.58 (dd, J = a-1.5): H5; 8.13 (s): H 2 + EtOH.

The following products were prepared using the appropriate amines as described above:

Example 4: 11,12-dideoxy 3-de {(2,6-dideoxy-3-C-methyl-3-Omethyl-alpha-L-ribohexoyranosyl) oxy) 6-O-methyl 3-oxo 12,11- ( oxycarbonyl) ((4- (thieno (2,3-b) pyridin-4-yl) butyl) imino)) erythroycin Bt = 176-178 ° C. .alpha _. = + 17 DEG C. c = 0.9% CHCl3

Example 5 11,12 -Dideoxy 3-de {(2,6-dideoxy-3-C-methyl-3-Omethyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11- (oxycarbonyl ((4- (3-phenyl 1H-1,2,4-triazol-1-yl) butyl) imino)) erythromycin

M.p. Mp = 208-210 ° C.

.alpha. = + 17 ° C · 1% in CHCl 3

Example 6: 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11- (oxycarbonyl ((4- (1-methyl-1H-imidazo (4,5-c) pyridin-2-yl) butyl) imino)) erythromycin alpha _D = + 19 ° C = 1% CHCl 3

Example 7: 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-Omethyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12.11- (oxycarbonyl ((4- (3-methyl-3H-imidazo (4,5-c) pyridin-2-yl) butyl) imino)) erythromycinaldehyde + 16 ° CHCl 3 = 1%

Example 8: 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-Omethyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12.11- (oxycarbonyl ((4- (7-methoxy-4-quinolinyl) butyl) imino)) erythromycin alphao = + 15.8 ° c = 1% CHCl 3

Example 9: 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12.11- (oxycarbonyl ((4- (5-phenyl-1H-tetrazol-1-yl) butyl) imino)) erythromycin.

Mp = 132 - 134 ° C. al.fa. _D = + 25 ° C = 1% CHCl 3

Example 10: n _- 12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-Omethyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11- (oxycarbonyl ((4- (2-benzothiazolyl) butyl) imino)) erythromycin

Mp = 179-181 ° C alpha. _D = + 18 ° C = 1% CHCl 3

Example 11: 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo-1,2. 11.1-7- (oxycarbonyl) ((4- (2- (3-pyridinyl) -4-thiazolyl) butyl) imino) erythromycin .

Mp = 150-152 ° C; Al _D = + 17 ° C = 0.9% CHCl 3

Example 12 = 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11- (oxycarbonyl ((4- {2- (3-pyridinyl) 5-thiazolyl) butyl) imino)) erythromycin,

M.p. = 155-159 ° C

J Λ ή

Example 13: 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-Omethyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11- (oxycarbonyl ((4- (9H-purin-9-yl) butyl) imino)) erythromycin

Example 14 _; 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-Omethyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11- (oxycarbonyl ((4- (1H-imidazo (4,5-c) pyridin-1-yl) butyl) imino)) erythromyoin.

Rf. = 0.42 CHCl 3 + 8% of MeOH with 8% of NH 4 OH

Example 15: 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11- (oxycarbonyl ((5- (1H-benzimidazol-1-yl) pentyl) imino)) erythromycin

Prepared from 2- (4-bromophenyl) -1H-iso-indole 1,3 (2H) -dione.

Example 16: 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-Omethyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11- (oxycarbonyl ((5-chloro-1H-benzimidazol-1-yl) butyl) imino)) erythromycin ^: mp = 1.45-148 ° C.

Example 17: 11, q 2-Dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 12,11 (oxycarbonyl (( 4- (1H-indol-1-yl) butyl) imino) erythromycin

Example 18: ~ ΐ j, i-2 3-ďiaéoxý ™ d'Etat (2Z GTdideoxy ^{cKmethyl-S-I-1} '' methyl-.alpha.-L-ribohexopyranosyl) oxy) 6-O-methyl 12,11 (oxycarbonyl ((4- (1-methyl-1H-indol-4-yl) butyl) imino)) erythromycin alpha, _D = 20%, c = 1% CHCl 3

Example 19: 11,12-dideoxy 3-de {(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12.11- (oxycarbonyl (<4- (2-phenyl-4-quinolinyl) butyl) imino)) erythromycin

M.p. MP 195-197 ° C.

Example 20: n, 12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12.11- (oxy-arbonyl ((4- (1H-benzotriazol-1-yl) butyl) imino)) erythromycin

M.p. 200-202 ° C.

Example 21 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-Omethyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12.11- (oxycarbonyl ((4- (2H-benzotriazol-2-yl) butyl) imino)) erythromycin

M.p. Mp = 164-166 ° C.

Example 22 12 -Dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12.11- {oxycarbonyl ((4- {5,6-dimethyl-1H-benzimidazol-1-yl) butyl) imino)) erytromycin

M.p. M.p. = 174-176 ° C.

Example 23: 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-Omethyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12.11- (oxycarbonyl ((4- (3-, inolinyl) butyl) imino)) erythromycin

M.p. MP 195-197 ° C.

Example 24: 11,2-Dideoxy 3-de ((2, G-dideoxy-S-C-methyl-S-Omethyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12.11- (oxy arbonyl ((4- (2-. Inolinyl) butyl) imino)) erythromycin

M.p. MP 179-181 ° C.

Example 25: 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-Omethyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12.11- {oxycarbonyl ((4- (2-methyl-1H-benzimidazol-1-yl) butyl) imino)) erythromycin

M.p. Mp 128-132 ° C.

Example 26: 11,12-Didedxy 3-de ((2,6-dideoxy-3-C-methyl-3-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12.11- (oxycarbonyl ((4- (6-chloro-1H-benzimidazol-1-yl) butyl) imino)) erythromycin

M.p. MP 192-194 ° C.

Example 27: π, 12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11- (oxycarbonyl ((4- (1-methyl-1H-benzimidazol-2-yl) butyl) imino)) erythromycin

Example 28: 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12.11- (oxycarbonyl ((4- (5H-imidazo (4,5-c) pyridin-5-yl) imino)) erythromycin alpha) = 12.2 c e = 1% CHCl 3

Example 29: 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12.11- (oxycarbonyl {(4- (4- (4-chlorophenyl), 1H-imidazol-1-yl) butyl) imino)) erythromypin 11-deoxy 10,11-didehydro 3-de (2,6-dodeoxy 3) -C-methyl

-3-O-inephthyl-1-a-1-pha L = ribohexo.p.yr.anpsyl. 12 (07 (1 H (Midazol-1-yl) carbonyl) 6-O-methyl 3-oxo-erythromycin 2'-acetate prepared as described in Example IC of European Patent Application EP 0, 596, 802 is heated to 75 ° C for 7 hours in 4 cm acetonitrile with 10% water with 1.4 g of 4- (4- (4-chlorophenyl) 1H-imidazole) butanamine. The reaction mixture was allowed to cool to ambient temperature, diluted with water, extracted with ethyl acetate, then dried, the solvent was evaporated, yielding 2.3 g of the product acetylated at the 2 'position. Methanol (60 ml) was added and the mixture was stirred for 16 h, the solvent was evaporated, the residue was chromatographed on silica gel (eluent: CH 2 Cl 2 -MeOH-NH 4 OH 95-5-0.4), concentrated and the residue was crystallized from the ether. The crystallized product is dried under reduced pressure at 80 ° C to give 381 mg of the expected product. M.p. = 192 -194 ^ 0.

NMR CDCl 3 ppm

0.83 (t): CH 3 -CH 2; 1.00 (d) ~ 1.16. (d) -1.24 (d) -1.30 (d) -1.38 (d). CH 3 -C 3 groups 1.33 (s) -1.47 (s): 6 and 12 Me; 2.26 (s): N (Me) ₂ ; 2.44 (m): H 3; 2.61 (s): 6-OMe; 2.60 (m); H ₈ ; 3.00 3.21: H4, H10 and H '₂; 3.55 (m): H 5; 3.56 (s): Hn; 3.60 to 3.80 2H-3.99 (t) 2H: _CH2 NC; 3.87 (q): _H2; 4.23 (d): H 5; 4.28 (d): H 1; 4.93 (dd): H ₁₃ ; 7.26 (d): H ₅ imidazole; 7.50 (d)

H ₂ imidazole; 7.32-7.70: aromatics; 3.51: OH.

Preparation of 4- (4-chlorophenyl) 1H-imidazole 1-butanamine used in Example 29

Step A: 4- (4-chlorophenyl) 1H-imidazole

23.34 g of bromo 4-chloro acetophenone in 150 ml of formamide are stirred under reflux for 1 hour; The reaction mixture was cooled, basified with sodium carbonate solution, extracted cficftToYměthaneHr, -extra-kfey ~ - is -. _____ washed with water, dried, the solvent evaporated, the residue is chromatographed on silica gel (eluant: CH ₂ Cl ₂ -MeOH-NH (OH-8-2-0.04) to give 13.4 g of the desired product. Bt 146-148 C.

Step B: 2- (4- (4- (4-chlorophenyl) 1H-imidazol-1-yl) 1H-iso indole-1,3 (2H) -dione

The procedure was carried out as in Step A of Preparation of Example 1 using 12.2 g of the product obtained in Step A, 4.96 g of sodium hydride and 23.83 g of N-4-bromobutylphthalamide. 9.7 g of the expected product are obtained.

Step C: 4- (4-chlorophenyl) 1H-imidazole 1 butanamine.

The procedure is carried out as in Step B of Preparation of Example 1 using 14.2 g of the product obtained in Step B as described above and 3.6 ml of hydrazine hydrate in 300 ml of ethanol. 12 g of crude product are obtained, which is chromatographed on silica gel (eluent: CH2Cl2-MeOH-NH4OH 8-2-0.04) and used as such for synthesis.

NMR (CDCl ₃₎ ppm;

1.22 (ws): mobile 2H! 1-47 (m) -1.88 (m): 2 center group CH ₂

2.74 (m): _{CH2 --CH2} --N; ³ · ^9δ = CN-CH ₂ -CH ₂ ?

II ¹ -C =

7.19 (d, J = 1.5); -7.50 (d, J = 1.5); H ₂ ~ a. H ₅ ; 7.33 d 7.70:

aromatics. '

Example 30: 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl 1-3-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11- (oxy arbonyl ((4- (4- (2-methoxyphenyl) 1H-imidazol-1-yl) butyl) imino)) erythromycin

706 mg of the starting compound of Example 29 (obtained as described in Example IC of European Patent Application EP 0,596, 802) in 3 ml of acetonitrile and 908 mg of 4- (4- (2-methoxyphenyl) 1H-imidazol-1-yl) butanamine The reaction mixture was allowed to cool to ambient temperature, then poured into a solution of sodium phosphate acid (0.5M), extracted with ethyl acetate, and the extracts washed water, dried, solvent evaporated; 1.6 g of product acetylated at position 2 'are obtained. Add 50 mL of methanol and stir for 16 h; then the solvent is evaporated, the residue is chromatographed on silica gel (eluent: AcOEt-TEA at 4¾) and crystallized from ether. 194 mg of the expected product are obtained.

M.p. = 143-145 ° C

NMR CDCl 3 ppm

0.85 (t): CH 3 -CH 2; 1.01 (d) -1.16 (d) -1.24 (¢) -1.30 (¢) -1.37 (d): groups 0 ^ -0 ^ 1.34 (s) -1.47 (s): 6 and 12 Me; 2.26 (s); N (Me) ₂ ; 2.44 (m): H 3; 2.60 (m): _H8; 2.64 (s): 6-OMe; 3.08 (m): H 4; 3.12 (wq): _H10; 3-1? (cod): H '₂; 3.54 (m): H 5; 3.57 (s): Hn; 3.66 (m) -3.74 (m): _CH2 NC;

3.85 (q): _H2; 3.95 (s): 0-0Me; 3.99 (wq): _CH2 -N =; 4.24 (d): H _S; 4.27 (d): H 1; 4.93 (dd): _K13 ; 6.97 (wd): Hg; 7.51 (s):

imidazoles H's; 7.02: phenyl 'Hg; 7.19 (ddd) phenyl H 4 and H ₅ ; 8.19 (dd): H _2nd

Preparation of 4- (2-methoxyphenyl) 1H-imidazole-1-butanamine used in Example 30. -,

Step A: 4- (2-methoxyphenyl) 1H-imidazole

9.36 g of 2-bromo 2'-methoxyacetophenone in 50 ml of formamide are heated to reflux, then the reaction mixture is allowed to cool to ambient temperature, washed with 2N hydrochloric acid solution, filtered, basified to pH 8-9 with 2N sodium carbonate, The crystals were washed out with water and dried, evaporated. The solvent and residue were chromatographed on silica gel (eluent: CH 2 Cl 2 -MeOH-NH 4 OH 95-5-0.4) to give 6.15 g of the desired product.

Step B: 2- (4- (4- (2-methoxyphenyl) 1H imidazol-1-yl) butyl) 1H-indole-1,3 (2H) -dione

The procedure is carried out as in Step A of Preparation of Example 1 using 6 g of the product obtained in Step A, 1.99 g of sodium hydride and 9.93 g of N-4-bromobutyl phthalimide. 6.15 g of the expected product is obtained.

Step C: 4- (2-methoxyphenyl) 1H-imidazole 1-butanamine (fumarate)

The procedure was carried out as in Step B of Preparation of Example 1 using 5.65 g of the product obtained in Step B and 1.45 ml of hydrazine hydrate in 75 ml of ethanol. Dissolve 3.8 g of the crude product in 4 ml of tetrahydrofuran and then add 1.87 g of fumaric acid in a solution of 20 ml of methanol. 10 ml of ether are added, the crystals formed are separated, dried at 80 DEG C. under reduced pressure to give 3.77 g of the expected product fumarate. Mp = 160-162 ° C.

NMR (CDCl 3) ppm

1.48 (m) 2H-1.87 (m) 2H: Whose centr.skupiny ^ 3.46: NH 2; 2.73 (t): _CH2 N; 3.94 (s): J-OMe; 3.97 (t): _CH2 NC; 6.94 (dd): Hg;

7.04 (dt) -7.21 (ddd): _H5 a. H4; 7.51: H- ₂ and H- ₅ ; 8.19 (dd): H _2nd

Example 31: 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11- (oxycarbonyl ((4- (4- (4-fluorophenyl) 1H-imidazol-1-yl) butyl) imino)) erythromycin

2.11 g of the starting compound of Example 29 (prepared as described in Example IC of the European Patent Application. 9 ml of acetonitrile and 2.8 g of 4- (4- (4-fluorophenyl) 1H-imidazol-1-yl) butanamine are heated at 60 DEG C. for 4 hours and 30 minutes. The reaction mixture was allowed to cool to room temperature, poured into water, extracted with ethyl acetate, the extracts washed with water, dried, the solvent evaporated to give 5.2 g of the product acetylated at the 2 'position. Add 20 mL of methanol, stir for 3 h and 30 min, evaporate the solvent, and chromatograph the residue on silica gel (eluent: CH

(K-MeOH-NHOH 95-5-0.3) and crystallized from ether.

1.34 g of the expected product is obtained. M.p. 190-192 ° C.

NMR CDCl 3 ppm

1.33 (s) -1.47 (s): 6 and 12 Me; 2.27 (s): N (Me) 2; 2.61 (s): 6-OMe; 3.0 to 3.18: H4 and Hiq; 3.56 (s): H-1; 3.59 to 3.81:

about 7.05 to about 7.73: fluorophenyl; 7.21 (d): H5 imidazole; 7.49 (d): imidazole H2.

Preparation of 4- (4-fluorophenyl) 1H-imidazole-1-butanamine used in Example 31

Step A: 4- (4-fluorophenyl) 1H-imidazole

10.85 g of 4-fluorophenacyl bromide in 60 ml of formamide are heated χ at reflux for 2 hours. The reaction mixture is allowed to cool to ambient temperature, acidified to pH 2 with N hydrochloric acid, then filtered, neutralized by addition of ammonium hydroxide, The residue is chromatographed on silica gel (eluent: Cl 2 -MeOH-NH 4 OH - 95-5-0.4) to give 5.8 g of the desired product. Mp = 130-132 * 0.

Step B: 2- (4- (4- (4-fluorophenyl) 1H-imidazol-1-yl) butyl) 1H-indole-1,3 (2H) dione ________, _________ The procedure of Step A of Preparation A of Example 1 was followed by using 10 g of the product obtained in Step A, 1.95 g of sodium hydride and 11.80 g of N-4-bromobutylphthalamide, 7.53 g of the expected product are obtained, mp = 138-140 ^(> C.

Step C: 4- (4-fluorophenyl) 1H-imidazole 1-butanamine

The process is carried out as in step B 'of the preparation of Example 1 under

· Use of 3.64 g of the product obtained in step B above and ml of hydrazine hydrate in 80 ml of ethanol. 2.4 g of crude oil are obtained. ! · ¹ <'product, which is * ^* chromatographed on silica gel (eluant: CH ^ CLJ -MeOH-NH? OH 8-2-0Ϊ03). The 'obtained' product is used for synthesis as such

-5 »

NMR (CDCl 3) δ ppm ^K -1- mp- 1.48- (m) -1781 (m): center -Λ of the CH 3 group) N-CH 33.98. ?

(t)> N-CH 2 CH _2; 7.06, (t): pCH-F, 7.2 µm): CH-C-;

7.49 (s): imidazole, H2; 7.15 (s); imidazole H5.

Example 32 11,12-dideoxy-3-de ((2,6-dideoxy-3-C-methyl-3-Omethyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11-phenyloxycarbonyl ({4- (7-methoxy (4-1-quinolinyl) butyl); imino)) _; , erythromycin. ,; ,; ··· ··%> ¹⁷⁰⁶ mg of the initial product of preparation 29 (prepared according to Example "IC Patent Application EP 0,596,8Ό2) in 4 mr ^r acetonitrile and 1.43 g 'of 4- (4-7-methoxy 4-quinoline The reaction mixture is allowed to cool to ambient temperature, poured into ^1: sodium phosphate acidic solution (0.5M), extraction is performed with dichloromethane, and the mixture is stirred at 50 ° C for 53 hours. the extracts were washed with water, dried, solvent ¹ was evaporated, yielding 1.0 g of the product acetylated at the 2 'position. Methanol (10 ml) was added, stirred for 16 h, the solvent was evaporated, the residue was chromatographed on silica gel (eluent: CH 3 Cl 2 -MeOH 95-5) and the ether was crystallized. 295 mg of the desired product are obtained.

M.p. = approx. Mp 110 ° C.

NMR CDCl 3 ppm ·.

3.0.6. (m): - (CH 2) ... 2 -CH 2; 3.70 (m), -N-CH ₂ -; 3.95 (s): - OCH3; 7.12 (d) -7.19 (dd) -7.42 (d) -7.94 (d) -8.70 (d): pyridine.

Preparation of 7-methoxy-quinoline 4-butanamine used in the example

Step A: triphenyl phosphonium salt of N- (3-bromopropyl) phthalimide

13.4 g of N-bromopropylphthalimide and 13.15 g of triphenylphosphine in a suspension of 75 ml of xylene are heated at reflux for 44 hours. The reaction mixture is allowed to cool to ambient temperature, the precipitate is separated, washed with ethyl ether and dried on reduced.

with.

24.88 g of the expected product are obtained. Mp = 220222 ° C.

Step B From (2-) 4- (7-methoxyquinolinyl) 3-butenyl 1H-isoindole-1,3 (2H) -dione

4g of 7-methoxy 4-quinolinylcarboxaldehyde is added to the suspension. 12.47 g of triphenylphosphonium salt of 3-bromopropyl phthalimide in 200 ml of tetrahydrofuran. The reaction mixture is cooled to -50 ° C, 2.72 g of potassium terbutyrate is added, the temperature is allowed to rise slowly to -6 ° C, then the mixture is filtered, the filtrate is concentrated, the residue is dissolved in ethyl acetate, washed with water, dried and solvent evaporates; then 9.26 g of crude product is obtained which is chromatographed on silica gel (eluent: CHCl 3 -AcOEt 80-20, then 70-30). 3.575 g of the expected product is obtained.

Step C: 2- (4- (7-methoxy-4-quinolinyl) butyl) 1H-isoindole 1,3 (2H) -dione

3.5 g of the product obtained in step B are dissolved in methanol, add 0.36 g of palladium on charcoal and hydrogenate the mixture at 600 mbar for 3 hours. . Filtration is carried out and the solvent is evaporated off to give 3.48 g of the expected product.

Step D: 7-methoxyquinoline-4-butanamine

3.46 g of the product obtained in Step C are dissolved in 70 ml of ethanol while hot, 1.86 ml of hydrazine hydrate are added, the reaction mixture is maintained at reflux for 17 hours, the precipitate is filtered off, the solvent is evaporated and the residue is dissolved in 70 ml of dichloromethane. filtration was carried out, the solvent was evaporated, yielding 2.19 g of the desired product.

NMR (CDCl 3) ppm

1.6 (m) - 1.79 (m): center group .; 2.75 (t):> -CH _{2 -} (CH ₂ ) 3; 3.05 (t): CH2 --NH2; 3.95 (s): O-CH3; 7.10 (d, J = 4.5) -7.21 (dd) - 7.92 (d) -8.71 (d, J = 4.5): quinoline

Example 33: 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12.11 (oxycarbonyl) ((4- (2 - (- pyridinyl) 4-thiazolyl) butyl) imino) erythromycin

705 mg of starting product of Example 29 (prepared as in Example 1C of European Patent application EP 0, 596, 802) in 3 mL of acetonitrile and 0.705 g of 4- (2- (2-pyridinyl 4-thiazolyl) -butanamine were heated at 60 C ^tf The reaction mixture was allowed to cool to ambient temperature, poured into water, extracted with ethyl acetate, the extracts were washed with water, dried, the solvent was evaporated, yielding 1.8 g of the product acetylated at the 2 'position. mL of methanol, the resulting mixture-SE- - warmed for - for-.refluxu. "po__dobu_2 hrs., the solvent was evaporated, the residue is chromatographed on silica gel (eluant: CH ₂ C1 _£ -MeOH-NH? OH - 95- 5-0.3, then AcOEt-TEA 9-1) and crystallized from ether to give 194 mg of the expected product.

M.p. Mp = 157-159 ° C.

NMR (CDCl 3) ppm

1.33 and 1.47: 6 and 12 Me; 2.26 (s): N (CH 3) 2; 2.86 (t);

CH 2 -C; 3.12 (wq): Hiq; 3.60 (s): Hn? 3.66 (m): CH2 --N - C;

II o

7.03 (s): thiazole _H5; 7.27 (ddd): pyridine H5; 7.77 (dt): pyridine H 4; 8.18 (dd) pyridine H3; 8.53 (ddd): pyridine Hg.

Preparation of 2- (2-pyridinyl) thiazole 4-butanamine used in Example 33.

Step A: 2-Aminocarbonylpyridine ml of a solution of diazomethane (0.4 M / L) was added dropwise to a solution containing 2 g of picolinic acid, 20 ml of dichloromethane and 5 ml of methanol. After 30 min. stirring this mixture at ambient temperature, the solvent was evaporated under reduced pressure, the residue was chromatographed on silica gel (petroleum ether (60-80) - AcOEt 5-5). to give 1.48 g of the methyl ester. 1.42 g of the ester are heated at 50 ^° C for 4 hours in 5 ml of ammonium hydroxide, the reaction mixture is allowed to cool to ambient temperature, extraction is performed with ether, the extracts are washed with water, dried, the solvent is evaporated to give 1.05 g. of the desired product. Mp = 105 ° C. .

Step B: Phosphorus pentasulfide 2-pyridinecarbothioamide g is slowly added to the 46.8 g amide obtained in Step A in 700 ml of tetrahydrofuran. Stir for 4 hours at room temperature, pour the reaction mixture into water / extract with ether, extract, dry, and remove the solvent under reduced pressure. . After chromatography on silica gel (eluent: CH 2 Cl 2 -AcOEt 8-2), 10 g of the expected product is obtained. Bt «137 ^tf C.

Step C: ethyl 2- (2-pyridinyl) 4-thiazole carboxylate

16.3 ml of ethyl bromopyruvate is added dropwise to 15.9 g of the product prepared in Step B in 250 ml of ethanol and the mixture is heated at reflux for 5 hours. The solvent is evaporated under reduced pressure, the residue is chromatographed on silica gel (eluant: hexane-AcOEt). 1-1) to give 10.2 g of the desired product. M.p. - 69.1 C.

Step D: 2- (2-pyridinil) 4-thiazolmethanol.

ml of methanol is slowly added to a mixture containing 9.3 g of the ester prepared in step C and 4.1 g of sodium borohydride in 100 ml of tetrahydrofuran and the mixture is heated at reflux for 2 hours. The reaction mixture is allowed to cool to room temperature, poured into water, neutralized with N hydrochloric acid, extraction is performed with dichloromethane, the organic phase is dried and the solvent is evaporated off under reduced pressure, the residue is chromatographed on silica gel (eluent: AcOEt-CH Cl-1-1) to give 5.8 g of the desired product. M.p. - 100 C.

Step E: 2- (2-pyridinyl) 4-thiazolecarboxaldehyde

5.8 g of the product prepared in Step D in 60 ml of toluene are heated at reflux for 2 hours in the presence of 13 g of manganese oxide, filtered, and the solvent is evaporated off under reduced pressure. 5 g of the expected product are obtained. Mp-131 C.

Step F. * (Y) 2- (4- (2- (2-pyridinyl) 4-thiazolyl) 3-butenyl) 1H-isoindole 1,3 (H) -dione

The process is carried out as in Step A and Step 5.70 g of the aldehyde prepared in Step E above and 15.9 g of triphenylphosphonium salt N are employed. - (3-bromopropyl) phthalimide and 3.70 g potassium terbutylate. 8.73 g of the expected product are obtained. M.p.

= 139-141 C.

Step G: (2- (4- (2-pyridinyl) 4-thiazolyl) butyl) 1H-isoindole 1,3 (2H) -dione)

The process is carried out as in Step B of Preparation 32 with 7.22 g of the product prepared in Step F above and 1.5 g of palladium on charcoal. Hydrogenation for 2 hours at 1800 mbar. 6.33 g of the expected product is obtained. Mp = 119-121 ° C.

Step H: 2- (2-pyridinyl) thiazole-butanamine

The process is carried out as in Step C of Preparation 32 using

5.45 g of the product obtained in Step G above and 1.6 ml of hydrazine hydrate, the mixture being heated at reflux for 6 hours. The solvent was evaporated, the residue was dissolved in ethyl acetate, washed with water, dried, the solvent was evaporated, the residue was chromatographed on silica gel (eluent: CH 2 Cl 2 -MeOH-NH 4 OH 9-1-0.03) to give 1.65 g of the desired product.

NMR (CDCl 3) ppm

1.50 (m) - 1.82 (m): cent. CH ₂ 2.76 (t) - 2.85 (t): CH ₂ -C CH and CH ₂ -NH ₂ ; 7.85 (s): thiazole H5; 7-31 (m): H 5; 7.78 (dt): H 14; 8.18 (dt): H 13; 8.61 (ddd); 1.40 (s): NH ₂ .

Example 34: 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-Omethyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11- (oxycarbonyl ((4- (4- (3-pyridinyl) 1H-imidazol-1-yl) butyl) imino) ') ---- --------------------- 1 g of the starting compound of Example 29 (prepared as described in Example 1C of European Patent Application EP 0,596, 802) in 4 ml of acetonitrile and 936 mg of 4- (4- (3-pyridinyl 1H-imidazol-1-yl) butanamine) was heated at 70 ° C for 20 h. The reaction mixture was allowed to cool to room temperature, poured into water, extracted with ethyl acetate. The extracts were washed with water, dried, the solvent was evaporated, yielding 1.34 g of the product acetylated at the 2-position, 40 ml of methanol were added, stirred for 2 hours, the solvent was evaporated and the residue chromatographed on silica gel (eluant: CH 2 Cl 2 -MeOH-NH 3 OH 95-5-0.4), crystallized with ether to give 310 mg of the desired product BT-187-188-4.

NMR (CDCl 3) ppm

0.83 (t): CH 3 -CH 2; 1.01 (d) -1.17 (¢3) -1.25 (¢3) -1.31 (d) -t. 38 (d) CH 2 -CH 1 - 34 (s) -1.47 (s): 6 and 12 Me; 2.27- (s):

N (Me) ₂ ; 2.45 (m): H 3; 2.62 (s): 6-OMe; 2.60 (π): Ηθ; 2.85 to 3.25: H _{4 and} H ₁₀ , H '₂; 3.52 (m): H 5; 3.56 (s): H1; 3.60 a 3.85 (m): _CH2 NC; 4.23 (d): _H5; if

4.27 (d): H 1; 4.93 (dd): H 13; 7.29 (ddd): pyridine H5; 8.08 (dt): pyridine H 4; 8.45 (dd): pyridine Hg; 8.97 (dd): pyridine. H ₂ ; 7.35 (d) and 7.53 (d): imidazole _H2 A- 'H5.

Preparation of (4- (3-pyridinyl) 1H-imidazole-1-butanamine used in Example 34)

Step A: 2- (4- (3-pyridinyl) 1H-imidazol-1-yl) butyl 1H-iso indole-1,3 (2H) -dione

The procedure is carried out as in Preparation Preparation Step A, Example 1, starting with. using 290 mg of 3-pyridinyl 1H-imidazole prepared as described in J.Chem.Soc. 753-5 (1938), 115 mg sodium hydride and 633 mg

N-bromobutyl tertiary amide yields 277 mg of the desired PEP.

Mp = 150-152 * 0.

Step B (3-Pyridinyl) 1H-imidazole 1-butanamine

The procedure is carried out as in Step B of Preparation of Example 1 using 1.66 g of the product prepared as in Step A above and 0.46 ml of hydrazine hydrate in 30 ml of ethanol. 936 mg of product are obtained, which product is used as such in the synthesis.

NMR (CDCl 3) ppm

1.49 (m) - 1.89 (m): center, CH = 2.75 (t): CH2 --CH2 --N;

AND

4.01 (t): = CN- ^CH 2 ^-CH 2;

I = C 7.29 (d, J = 1) -7.55 (d, J = 1): H2 and H5; 7.30 (partially masked H'5; 8.09 (dt, J = 8 and 2): H'4; 8.47 (dd, J = 5 and 2): H '₆;

8.96 (d, J = 2): H'2, ´ 1.49 (wsj: approx. 2H's mobile).

Example 35: 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11- (oxycarbonyl ((4- (3- (3-pyridinyl) 1H-1,2,4-triazol-lyl) butyl) imino)) erythromycin g of the starting product of Example 29 {prepared as described in Example 1C of European of patent application EP 0 596, 802) in 4 ml of acetonitrile and 1.21 g of 4- (3- (3-pyridinyl 1H-1,2,4-triazol-1-yl) butanamine) are heated at 75 ° C for 8 hours. The mixture is allowed to cool to ambient temperature, poured into water, extracted with ethyl acetate, the extracts are washed with water, dried, the solvent is evaporated, yielding 2 g of the acetylated product at the 2 'position. After 16 h, the solvent was evaporated, the residue was chromatographed on silica gel (eluent: CH 2 Cl 2 -MeOH-NH 4 OH 90-10-0.04) and crystallized from ether to give 292 mg of the desired product. -192 * 0.

NMR (CDCl 3) ppm

0.84 (t): CH 3 -CH 2; 1.01 (d): OMe; 1.16 (d): 8 Me; 1.25 d

5Me; 1.30 (d): 4Me; 1.34 (d): 2Me; 1.33 (s) and 1.47 (s): 6 and 12 Me; 1.67 (m) -1.99 (m): CH _{2 center group} 2.26 (s):

N (Me) ₂ ; 2.44 (m): H- ₃ ; 2.58 (m): Hg; 2.61 (s): 6-OM? 3.06 (m): H 4; 3.12. <q>: H _lo ; 3.17 (dd): H- ₂ ; 3.52 (m): H- ₅ ; 3.56 (s): Hn; 3.64 3.75 a (-): _CH2 NC;

O

3.85 (q): _H2; 4.25; Η'-j, Hg and 'CH ₂ NC;

4.91 (dd): H 13; 8.15 (s): triazole H; 7.35 (dd): pyridine. H5; 8.34 (dt): pyridine H ₄ ; 8.62 (dd): pyridine Hg; 9.31 (wd): pyridine H _2nd

Preparation of 3- (3-pyridinyl) 1H-1,2,4-triazole-1-butanamine used in Example 35

Step A: 2- (4- (3- (3-pyridinyl) 1H-1,2,4-triazol-1-yl) butyl) 1H-isoindole-1,3 (2H) -dione.

The procedure was carried out as in Step A of Preparation of Example 1 using 2.1 g of 3-pyridinyl 1H-1,2,4-triazole prepared as described in J. Org. Chem. (44) No. 33, 4160-4164 (1979). 1.02 g of sodium hydride and 4.13 g of N-4-bromobutylphthalimide. 2.4 g of the expected product are obtained.

Step B: 3- (3-pyridinyl) 1H-1,2,4-triazole-1-butanamine

The procedure is carried out as in Step B of Preparation of Example 1 using 3.46 g of the product obtained in Step A above and 1 ml of hydrazine hydrate in 50 ml of ethanol. 2.1 g of crude product are obtained, which is converted to the fumarate as described in Preparation 30 and then 1.13 g of the desired product fumarate. Bt - approx. 190192 ^P C.

NMR (CDCl 3) ppm

1.50 (m) -2.01 (m): CH ₂ 'center 2.76 (fc): NH 2 -CH 2 -;

4.24: = N-N-CH 2; 7.37 (ddd), H5; 8.35 (dt): H 4; 8.63 (dd): Hg; 9.32 (dd) H2; 8.12 (s): triazole = CH.

The following products were prepared using the appropriate amines as described above:

Example 36: 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11- (oxycarbonyl {(4- (3-quinolinyl) butyl) imino)) erythromycin

Bit. Mp = 190-192 ° C.

Example 37: 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-Omethyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11- (oxycarbonyl ((4- (4- (4-methoxyphenyl) 1H-imidazol-1-yl) butyl) imino)) erythromycin »

M.p. MP 152-154 ° C.

Example 38: 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12.11 - (oxycarbonyl ({4- (2-phenyl-4-thiazolyl) butyl) imino)) erythromycin

M.p. MP 141-143 ° C.

-----..Example. 3.9 ...: 44., 4-Dideoxy-3-de (- (- 2-, 6-dideoxy-3-G-meth-1-3-O-methyl-alpha-L- ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11- (oxycarbonyl ((4- (4- (3-methoxyphenyl) 1H-imidazol-1-yl) butyl) imino)) erythromycin. mp = 144-146 ° C.

Example 40: 11,12-dideoxy 3-de {(2,6-dideoxy-3-C-methyl-3-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11- (oxycarbonyl ((4- (4,5-diphenyl. 1H-imidazol-1-yl) butyl) imino)) erythromycin

M.p. MP 180-182 ° C.

Example 41: 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11- (oxycarbonyl ((4- (4-quinazolinyl) butyl) imino)) erythromycin

M.p. MP 212-214 ° C.

Example 42: 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11- (oxycarbonyl ((4- (2- (4-pyridinyl) 4-thiazolyl) butyl) imino)) erythromycin

M.p. MP 192-194 ° C.

Example 43: 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11- (oxycarbonyl ((4- (1,2,3,6-tefrahydro-1,3-dimethyl 2,6-dioxo-7H-purin-7-yl) butyl) imino)) erythromycin B.t. Mp = 251-253 ° C.

Example 44: π, _Ί 2 _-Dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo

12,11- (oxycarbonyl {{4- (4- (4-trifluoromethoxy) phenyl) -1H * imidazol-4-yl) butyl) imino} erythromycin M.p. = 168-170 ° C

The amines used as starting products are prepared according to the following methods:

A- If the chain is connected to carbon e.g.

the corresponding aldehydes can be started

«2

-►

Pd

Het 'Amines' used for the preparation of the products according to the invention,

11, 12, 18, 19, 23 and 24 were thus prepared.

B- When the chain is attached to nitrogen, the amines can be prepared as follows.

He t NH

The amines used to prepare the products of Examples 1, 2, 3, 5, 9, 13, 14, 15, 16, 17, 20, 21, 22, 25, 26 and 28 were prepared in this manner.

C- Certain amines were prepared in a special way:

the heterocycle is formed and the chain is introduced at the same time (Example 6, 7, 10 and 27).

Examples of pharmaceutical compositions

Compounds containing:

product according to example 1 ............................... 150 mg excipient ........... ................................................ 1 excipient data: starch, talk, magnesium stearate products according to example 2 ............................... 150 mg excipient ............... ............................... 1 9 excipient data: starch, talk, magnesium stearate product according to example 3 ... ........................... 150 mg excipient ................... ........................... 1 9 excipient data: starch, talk, magnesium stearate

Pharmacological study of the products according to the invention

Method of dissolution in liquid medium

A series of test tubes is prepared in which an equal amount of sterile nutrient medium is distributed. A number of products are dispensed into each tube and gradually increased and each tube is inoculated with a bacterial strain. After incubation in a chamber heated to 37 ° C, the growth inhibition of transillumination is evaluated to determine the minimum inhibitory concentrations expressed in micrograms / cm ³ . The following table summarizes the results achieved:

The products of Examples 1, 2 and 3 show useful activity against the following gram-positive bacterial strains: Haemophilus Influenzae 351HT3, 351CB12 and 351GR6.

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Claims (6)

Patent claims An erythromycin derivative of the formula (I) (I) wherein R represents a (CH ₂ ) _n Ar radical in which n represents 3,4 or 5 and Ar represents a heterocyclic radical optionally with one or two substituents selected from the following radicals: wherein Z 'is an acid residue, reacts with a compound of formula (III) rnh ₂ (III) wherein R is as defined in claim 1, to prepare a compound of formula (1) wherein R and Z' have their previous meanings, and is if desired, the compound of formula (I) is treated with a hydroxyl releasing agent at the 2 'position and / or, if necessary, treated with an acid to form a 15. Compounds of formula. (III) as defined in claim 14. 16.Amines of compounds of formula (III) as defined in claim 15 of the title: - 4-phenyl-1H-imidazole. 1-butanamine, - 3H-imidazo (4,5-b) -pyridine 3-butanamine - 1H-imidazo (4,5-b) -pyridine-3-butanamine, - 2-Phenyl-4-quinoline butanamine, 4 * * 1 -___ -. 1 _hiiHnsmi n. - Π, 1 2-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methylalpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,41 (oxycarbonyl ( (4- (2- (2-pyridinyl) 4-thiazolyl) butyl) imino) erythromycin, - 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methylalpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11 (oxycarbonyl (( 4- (3- (3-pyridinyl) 1H-1,2,4-triazol-1-yl) butyl) imino) erythromycin. New chemical product, a compound according to formula (I) as defined in claim 1 of the title: - 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-hexohexopyranosyl) oxy) 6-O-methyl-3-oxo 12,11- (oxycarbonyl ( (4- {4- (3-pyridinyl) 1H-imidazol-1-yl) butyl) imino) erythromycin. 10. Compounds of formula (I) as defined in any one of claims 1 to 7, as well as their addition salts. salts with pharmaceutically acceptable acids as medicaments. Compounds as defined in claim 8, as well as their addition salts with pharmaceutically acceptable acids as medicaments. A compound as defined in claim 9, as well as its addition salts with pharmaceutically acceptable acids as medicaments. Pharmaceutical compositions comprising as active ingredient at least one medicament according to any one of claims 10 to 12. A process for the preparation of compounds of formula (I) as defined in claim 1, characterized in that the compound of formula (II) N O n 9 'optionally substituted. New chemical products, derivatives according to formula (I) as defined in claim 1, whose names are; - 11,1 2-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methylalpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11 (oxycarbonyl ( (4- (4-phenyl-1H-imidazol-1-yl) butyl) imino) erythromycin, - 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methylalpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,1.1 (oxycarbonyl (( 4- (3H-imidazo (4,5-b-pyridin-3-yl) butyl) imino) erythromycin- - 11,12-dideoxy 3-de {(2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11 (oxycarbonyl {( 4- (1H-imidazo (4,5-b-pyridin-1-yl) butyl) imino) erythromycin, - 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methylalfar-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11 (oxycarbonyl (( 4- (4- (4-chlorophenyl) 1H-imidazol-1-yl) butyl) imino) erythromycin, - 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methylalpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11 - (- oxy -carbonyl ((4- (4 - (- 2-methoxyl.phenyl ..) ... .alpha.-imazazol-1-yl)), .......... ...... butyl) imino) erythromycin, - 11,12-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methylalpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11 (oxycarbonyl (( 4- (4- (4-fluorophenyl) 1H-imidazol-1-yl) butyl) imino) erythromycin, - 11,1 2-dideoxy 3-de ((2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-ribohexopyranosyl) oxy) 6-O-methyl 3-oxo 12,11 (oxycarbonyl ( (4- (7-methoxy-4-quinolinyl) butyl) imino) erythromycin, a radical or R is and Z is a hydrogen atom or an acid residue, as well as their acid addition salts. The erythromycin derivatives of formula (I) as defined in claim 1, wherein Z represents a hydrogen atom. The erythromycin derivatives of formula (I) as defined in claim 1 or 2, wherein n is 4. Erythromycin derivatives according to formula (I) as defined in claim 1, 2 or 3, wherein Ar represents a radical: N optionally substituted. The erythromycin derivatives of formula (I) as defined in claim 1, 2 or 3, wherein Ar is a radical N N optionally substituted. The erythromycin derivatives of formula (I) as defined in claim 1, 2 or 3, wherein Ar is a radical;